The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis
Cp. Schneider et al., The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis, SHOCK, 14(3), 2000, pp. 347-353
Citations number
27
Categorie Soggetti
Aneshtesia & Intensive Care","Cardiovascular & Hematology Research
Studies have shown that immune responses are depressed in male mice, but no
t in proestrus females after trauma-hemorrhage (TH), resulting in increased
mortality from subsequent sepsis in male mice compared with female mice. T
hese gender-specific alterations in immune function are believed to be due
to differences in sex steroid levels. Aromatase is a key enzyme in the sex
steroid biosynthesis. Although earlier studies have shown that aromatase in
hibitors prevent thymic atrophy in aged male rats, it remains unknown wheth
er the use of 4-hydroxy-androstenedione (4-OHA) after TH in male mice has a
ny salutary effects on the depressed immune responses. Male C3H/HeN mice we
re sham operated or subjected to trauma (i.e., midline laparotomy) and hemo
rrhagic shock (30 +/- 5 mmHg for 90 min) followed by adequate fluid resusci
tation, 4-OHA (5 mg/kg) or vehicle was administrated s.c. just before resus
citation. At 2 h after resuscitation, the mice were killed, and spleens wer
e harvested. Splenocyte proliferation, interleukin (IL-2), interferon (IFN-
gamma), and IL-10 release and expression of androgen (AR) and estrogen rece
ptors (ER)-alpha and -beta by immunoblot and reverse transcription-polymera
se chain reaction (RT-PCR) were assessed. In another group, sepsis was indu
ced by cecal ligation and puncture (CLP) 3 days after resuscitation, and su
rvival was measured over a period of 10 days. A significant decrease in spl
enocyte proliferation, IL-2, and IFN-gamma release and increased release of
IL-10 were observed in vehicle-treated mice. Animals treated with 4-OHA sh
owed increased splenocyte proliferation. IL-2, and IFN-gamma release, and d
ecreased IL-10 release. Immunoblot analysis showed decreased expression of
the cytosolic AR, but no significant difference in the cytosolic and nuclea
r ER-alpha and -beta expression was observed in the vehicle-treated group a
fter TH. In addition, AR and ER-beta mRNA expression was increased, whereas
ER-alpha expression decreased in the vehicle-treated group after TH, ER-al
pha expression decreased and ER-beta expression increased in the nucleus of
4-OHA treated mice as determined by immunoblot. There was no difference in
the cytosolic AR expression in the 4-OHA-treated group after TH. AR and ER
-beta mRNA expression was unaffected, whereas ER-alpha expression increased
under such conditions. In additional groups, the increased mortality rate
after TH and subsequent sepsis was significantly reduced by 4-OHA treatment
. Thus, 4-OHA seems to be a novel and useful adjunct for restoring the depr
essed immune functions in males after TH and for decreasing mortality rates
from subsequent sepsis.